Instructions for Tyfer solution for injection or concentrate for solution for infusion 20 mg/ml ampoules 5 ml No. 5
Composition
active ingredient: 1 ml of solution contains 20 mg of iron (in the form of iron (III) hydroxide sucrose complex);
Excipients: sodium hydroxide, water for injections.
Dosage form
Solution for injection or concentrate for solution for infusion.
Main physicochemical properties: dark brown colloidal solution.
Pharmacotherapeutic group
Antianemic agents. Iron preparations. ATC code B03A C.
Pharmacological properties
Pharmacodynamics.
The active ingredient of the drug Tyfer - iron sucrose - consists of polynuclear iron (III) hydroxide centers, surrounded on the outside by a large number of non-covalently bound sucrose molecules. The average molecular weight of the complex is approximately 43 kDa. The polynuclear iron center has a structure similar to the structure of the ferritin center, which is a physiological iron-containing protein. The complex is designed in such a way that the absorbed iron is delivered in a controlled manner to the proteins that ensure its transport and storage in the body (transferrin and ferritin, respectively).
After intravenous administration, the multinuclear iron center from the complex is taken up mainly by the reticuloendothelial system of the liver, spleen, and bone marrow. In the second stage, the iron is used for the synthesis of hemoglobin, myoglobin, and other iron-containing enzymes or is stored in the liver as ferritin.
Pharmacokinetics.
Distribution. The ferrokinetics of sucrose iron labeled with 52Fe and 59Fe were evaluated in 6 patients with anemia and chronic renal failure. During the first 6-8 hours, 52Fe is taken up by the liver, spleen, and bone marrow. Radioactive iron uptake occurs in macrophages of the reticuloendothelial system of the spleen.
After intravenous administration of a single dose of iron (III) hydroxide sucrose complex containing 100 mg iron to healthy volunteers, maximum iron concentrations were observed 10 minutes after administration and reached a mean value of 538 mmol/L. The volume of distribution in the central compartment corresponded to the volume in blood plasma (approximately 3 liters).
Metabolism: After injection, sucrose is almost completely broken down, and the multinuclear iron center is taken up mainly by the reticuloendothelial system of the liver, spleen, and bone marrow.
Within 4 weeks after administration, iron uptake by erythrocytes ranges from 68% to 97%.
Elimination. The average molecular weight of the complex is approximately 43 kDa and is large enough to avoid renal excretion. Renal excretion of iron during the first 4 hours after injection of 100 mg of iron is less than 5% of the administered dose. After 24 hours, total serum iron concentration has decreased to baseline (pre-administration) levels, and renal excretion of sucrose is approximately 75% of the administered dose.
Pharmacokinetics in specific patient groups. It is still unknown whether renal and hepatic insufficiency affect the pharmacological properties of iron (III) hydroxide sucrose complex (see section "Special instructions").
Indication
The use of the drug Tyfer is indicated for patients with iron deficiency for the following indications:
- if you are intolerant to oral iron preparations;
- in the presence of gastrointestinal diseases (ulcerative colitis), when oral iron preparations can provoke an exacerbation of the disease;
- in iron deficiency states resistant to therapy, when control of these states with oral iron preparations is insufficient.
Tyfer should only be used when the indications are based on appropriate studies. Appropriate laboratory tests include determination of hemoglobin, serum ferritin, and transferrin saturation.
Contraindication
- Known hypersensitivity to the active substance or to other components of the medicinal product.
- Anemia not associated with iron deficiency (e.g., hemolytic anemia, megaloblastic anemia due to vitamin B12 deficiency, impaired erythropoiesis, bone marrow hypoplasia, anemia caused by lead poisoning).
- Oversaturation of the body with iron (hemochromatosis, hemosiderosis) or hereditary disorders of iron absorption (sideroachrestic anemia, thalassemia, porphyria cutanea).
- First trimester of pregnancy.
Interaction with other medicinal products and other types of interactions
Tyfer is indicated for patients who cannot be prescribed oral iron preparations due to intolerance, ineffectiveness, or gastrointestinal disease. Tyfer should not be used concomitantly with oral iron preparations, as absorption of orally administered iron is reduced.
Application features
Intravenous administration of iron preparations may lead to immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions), which may be fatal. Such reactions have been reported even in cases where previous use of parenteral iron preparations was without complications. In patients who have experienced hypersensitivity reactions to iron dextran, Tyfer should be used only in cases of extreme necessity and with strict precautions.
Treatment with Tyfer should be prescribed by a doctor only after accurately determining the indication.
Tyfer should only be administered when medical personnel trained in the assessment and treatment of anaphylactic reactions are available for immediate response and in a facility equipped with resuscitation equipment. Before each administration of Tyfer, the patient should be questioned about any previous adverse reactions associated with intravenous iron.
Typical symptoms of acute hypersensitivity reactions are: decreased blood pressure, tachycardia (even anaphylactic shock), respiratory symptoms (including bronchospasm, laryngeal edema and pharyngeal edema), gastrointestinal symptoms (including abdominal cramps, vomiting) or skin symptoms (including urticaria, erythema, pruritus).
Each patient should be observed for adverse reactions at least 30 minutes after each intravenous administration of iron preparations. If any allergic reactions or signs of intolerance occur during administration of the drug, treatment should be discontinued immediately.
For emergency treatment of acute anaphylactic/anaphylactoid reactions, adrenaline, e.g. 0.3 mg intramuscularly, is recommended first, followed by antihistamines and/or corticosteroids (which have a later onset of action).
High risk of hypersensitivity reactions in patients with existing allergies, including drug intolerance, a history of severe bronchial asthma, eczema and other forms of atopy, as well as in patients with immunological and inflammatory diseases (systemic lupus erythematosus, rheumatoid arthritis).
Parenteral administration of iron to patients with hepatic dysfunction should only be considered after careful risk/benefit analysis. Parenteral administration of iron to patients with hepatic dysfunction should be avoided in cases where iron overload may be a precipitating factor. Close monitoring of iron levels is recommended to avoid iron overload.
Parenteral iron administration may negatively affect the course of bacterial or viral infection.
Parenteral iron preparations should be used with caution in patients with acute or chronic infection.
In patients with chronic infection, a benefit/risk assessment should be performed. It is recommended that Tyfer be discontinued in patients with bacteremia.
Paravenous leakage should be avoided, as Tyfer injection site exposure may result in pain, inflammation, tissue necrosis, and brown discoloration of the skin. In the event of paravenous leakage, the drug should be discontinued immediately.
A decrease in blood pressure is usually observed with the use of iron preparations for intravenous administration. Therefore, this drug should be used with caution. The recommendations for the rate of administration of Tyfer should be strictly followed to prevent the development of arterial hypotension. A higher incidence of undesirable side effects (especially the occurrence of arterial hypotension) is associated with an increase in the dose or rate of administration of this drug.
Special caution should be exercised when using the drug Tyfer in patients with hepatic insufficiency, decompensated cirrhosis of the liver, epidemic hepatitis, Randu-Osler disease, infectious kidney diseases in the acute phase, and uncontrolled hyperparathyroidism.
The drug Tyfer contains up to 7 mg of sodium in 1 ml.
Use during pregnancy or breastfeeding
Pregnancy.
There is some data on the use of iron sucrose complex in pregnant women in the first trimester of pregnancy. Data on the use of iron (III) hydroxide sucrose complex in pregnant women in the second and third trimesters of pregnancy showed no adverse effects on the health of the mother and child.
It is not yet known whether iron(III) hydroxide sucrose complex crosses the placenta. Iron bound to transferrin does not cross the placental barrier. Iron bound to lactoferrin passes into breast milk.
Studies on the effect on iron levels in newborns have not been conducted.
The risk/benefit ratio should be assessed before using the drug during pregnancy, as hypersensitivity reactions may carry a certain risk for the mother and child (see section "Special instructions"). Pre-pregnancy body weight should be taken into account to calculate the required amount of iron to avoid overdose.
Fetal bradycardia may develop after parenteral iron administration. This is usually transient and is a consequence of a hypersensitivity reaction in the mother. The unborn child should be carefully monitored when intravenous iron is administered to pregnant women.
Breastfeeding period.
Data on iron excretion in human breast milk after intravenous administration of iron sucrose are limited. In a clinical study, 10 healthy women with iron deficiency who were breastfeeding received 100 mg of iron in the form of a sucrose complex. After four days of treatment, the iron content in breast milk was not increased and did not differ from that in the control group (n = 5). An effect of iron in the mother's breast milk on the newborn/infant cannot be excluded, therefore the risk/benefit ratio of the drug should be assessed.
Ability to influence reaction speed when driving vehicles or other mechanisms
There are no relevant studies. The effect on the reaction rate when driving or using other mechanisms is unlikely. However, in case of adverse reactions such as dizziness, confusion after taking the drug, you should refrain from driving or using other mechanisms until the symptoms disappear.
Method of administration and doses
The drug Tyfer is administered only intravenously.
This medicine is not intended for subcutaneous or intramuscular administration.
Tyfer should only be used when the indications are based on appropriate studies. Appropriate laboratory tests include determination of hemoglobin, serum ferritin, and transferrin saturation.
Patients should be observed for signs and symptoms of hypersensitivity reactions during and after administration of the medicinal product. Appropriate emergency treatment should be provided (see section 4.4).
The total cumulative dose of the drug should be calculated for each patient individually and not exceeded. The dose is calculated taking into account the patient's body weight and hemoglobin level.
In cases where the total required dose exceeds the maximum permitted single dose of 200 mg (for injection) or 500 mg (for infusion), it is recommended to administer the drug in parts.
Dose calculation
The total cumulative dose of the drug Tyfer, equivalent to the total iron deficiency (mg), is determined taking into account the hemoglobin (Hb) level and body weight. The dose of the drug is calculated individually according to the total iron deficiency in the patient's body according to the Ganzoni formula:
Total iron deficiency (mg) = body weight (kg) ´ (normal Hb level (g/l) ‒ patient's Hb level (g/l)) ´ 0.24* + stored iron (mg).
For patients with a body weight of less than 35 kg: normal Hb level is 130 g/l, the amount of deposited iron is 15 mg/kg of body weight.
For patients with a body weight of more than 35 kg: normal Hb level is 150 g/l, the amount of deposited iron is 500 mg.
* Coefficient 0.24 = 0.0034 ´ 0.07 ´ 1000 (iron content in Hb = 0.34%, blood volume = 7% of body weight, coefficient 1000 = conversion of "g" to "mg").
| Total volume of drug to be administered (in ml) | = Total iron deficiency (mg) 20 mg iron/ml |
Table 1
Total cumulative dose of Tyfer (ml) to be administered, taking into account the patient's body weight and Hb level
| Body weight | Total dose of the drug Tyfer (20 mg iron/ml) for administration | | | |
| (kg) | Hb 6.0 g/dl | Hb 7.5 g/dl | Hb 9.0 g/dl | Hb 10.5 g/dl |
| 10 | 15.0 ml | 15.0 ml | 12.5 ml | 10.0 ml |
| 15 | 25.0 ml | 22.5 ml | 17.5 ml | 15.0 ml |
| 20 | 32.5 ml | 27.5 ml | 25.0 ml | 20.0 ml |
| 25 | 40.0 ml | 35.0 ml | 30.0 ml | 27.5 ml |
| 30 | 47.5 ml | 42.5 ml | 37.5 ml | 32.5 ml |
| 35 | 62.5 ml | 57.5 ml | 50.0 ml | 45.0 ml |
| 40 | 67.5 ml | 60.0 ml | 55.0 ml | 47.5 ml |
| 45 | 75.0 ml | 65.0 ml | 57.5 ml | 50.0 ml |
| 50 | 80.0 ml | 70.0 ml | 60.0 ml | 52.5 ml |
| 55 | 85.0 ml | 75.0 ml | 65.0 ml | 55.0 ml |
| 60 | 90.0 ml | 80.0 ml | 67.5 ml | 57.5 ml |
| 65 | 95.0 ml | 82.5 ml | 72.5 ml | 60.0 ml |
| 70 | 100.0 ml | 87.5 ml | 75.0 ml | 62.5 ml |
| 75 | 105.0 ml | 92.5 ml | 80.0 ml | 65.0 ml |
| 80 | 112.5 ml | 97.5 ml | 82.5 ml | 67.5 ml |
| 85 | 117.5 ml | 102.5 ml | 85.0 ml | 70.0 ml |
| 90 | 122.5 ml | 107.5 ml | 90.0 ml | 72.5 ml |
Table 2
Required Hb level depending on patient's body weight
| Body weight | Required Hb |
| 13 g/dl | |
| ≥ 35 kg | 15 g/dl |
To convert Hb (mM) to Hb (g/dl), the first indicator must be multiplied by 1.6.
If the required total dose exceeds the maximum permissible single dose of 200 mg (injection) or 500 mg (infusion), then the administration should be carried out in several doses.
Standard dosage
Adults
5-10 ml of Tyfer (100-200 mg of iron) 1-3 times a week. See below for application time and dilution ratio.
Children aged 3 and over
There are only limited data on the use of the drug in children. In case of clinical need, it is recommended to administer no more than 0.15 ml of the drug (3 mg of elemental iron) per 1 kg of body weight 1-3 times a week. For the time of administration and dilution factor, see below.
Maximum tolerated single or weekly dose
Adults
For injections, the maximum tolerated dose, which is administered no more than 3 times a week, is 10 ml of the drug (200 mg of iron), the duration of administration is at least 10 minutes.
For infusion, the maximum tolerated dose, administered no more than once a week to patients weighing more than 70 kg, is 500 mg of iron (25 ml of the drug) over at least 3.5 hours;
patients with a body weight of 70 kg and below - 7 mg of iron per 1 kg of body weight for at least 3.5 hours.
The infusion time should be strictly adhered to, even if the patient does not receive the maximum tolerated single dose.
If hematological parameters do not improve (an increase in hemoglobin level of approximately 1 g/L of blood per day or approximately 1.0–2.0 g/dL 1–2 weeks after the start of treatment), the patient's initial diagnosis should be reviewed and persistent blood loss should be excluded.
Application
The drug Tyfer can only be administered intravenously, by drip infusion, slow injection, or directly into the venous section of the hemodialysis machine.
The drug should not be administered intramuscularly or subcutaneously.
If the required total dose exceeds the maximum allowable single dose, the total dose should be divided into several doses.
Intravenous drip
Immediately before administration, Tyfer should be diluted only in sterile 0.9% sodium chloride solution according to the scheme specified in Table 3.
Table 3
Dosage of the drug Tyfer (mg iron) | Dose of the drug Tyfer (ml) | Maximum volume of sterile 0.9% sodium chloride solution for dilution | Minimum input time |
| 50 mg | 2.5 ml | 50 ml | 8 minutes |
| 100 mg | 5 ml | 100 ml | 15 minutes |
| 200 mg | 10 ml | 200 ml | 30 minutes |
| 300 mg | 15 ml | 300 ml | 1.5 hours |
| 400 mg | 20 ml | 400 ml | 2.5 hours |
| 500 mg | 25 ml | 500 ml | 3.5 hours |
Intravenous administration
The drug can be administered intravenously by slow infusion at a rate of 1 ml of undiluted solution per minute, but the maximum volume of the solution should not exceed 10 ml (200 mg of iron) per injection.
Paravenous leaks should be avoided, as drug entry at the injection site may result in pain, inflammation, tissue necrosis, and brown discoloration of the skin (see section "Special warnings and precautions for use").
Injection into the venous section of the dialysis system
The drug Tyfer can be administered directly into the venous section of the dialysis system during a hemodialysis session, strictly following the rules for intravenous injection.
Children.
Due to insufficient data, the use of Tyfer is not recommended for the treatment of children under 3 years of age.
Overdose
Overdose may lead to acute iron overload, which may manifest as hemosiderosis. In case of overdose, symptomatic therapy and, if necessary, iron-binding agents (chelates) are recommended.
Adverse reactions
The most common adverse reactions observed during clinical trials of iron (III) hydroxide sucrose complex are dysgeusia, which occurred at a frequency of 4.5 events per 100 people. Other common adverse reactions include nausea, hypotension, hypertension, and infusion site pain, which occurred at a frequency of 1 to 2 events per 100 people.
Adverse reactions are classified according to the frequency of occurrence into the following categories: common (<1/10 to ≥1/100), rare (1/100 to ≥1/1000) and very rare (1/1000 to ≥1/10000), frequency unknown (available data do not allow to estimate the frequency, since such events were reported exclusively during post-marketing studies).
On the part of the immune system
Rare: hypersensitivity reactions.
Metabolism and eating disorders
Rare: iron overload.
From the nervous system
Common: dysgeusia, dizziness.
Rare: headache, paresthesia, hypoesthesia.
Very rare: loss of consciousness, drowsiness.
From the side of the cardiovascular system
Rare: hypotension and collapse, tachycardia.
Very rare: bradycardia.
From the vascular system
Common: hypotension, hypertension.
Rare: thrombophlebitis, phlebitis.
Respiratory, thoracic and mediastinal disorders
Rare: shortness of breath.
Kidney and urinary system disorders
Very rare: chromaturia.
From the digestive tract
Common: nausea.
Rare: vomiting, abdominal pain, diarrhea, constipation.
Liver and gallbladder
Rare: increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyltransferase.
Very rare: increased levels of lactate dehydrogenase in the blood.
Skin and subcutaneous tissue disorders
Rare: itching, rash.
Musculoskeletal and connective tissue disorders
Rare: muscle cramps, myalgia, arthralgia, pain in extremities, back pain.
General disorders and administration site conditions
Common: injection site reactions1.
Rare: chest pain, chills, asthenia, fatigue, peripheral edema, pain.
Very rare: increased sweating, fever.
1 The most commonly observed adverse reactions are: pain, extravasation, irritation, injection site reactions, skin discoloration, hematoma, and pruritus at the injection/infusion site.
The following adverse reactions have been reported in voluntarily submitted post-marketing reports:
Frequency unknown: confusion, bradycardia, thrombophlebitis.
Reporting of suspected adverse reactions
Reporting adverse reactions after registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of a medicinal product to the State Expert Center of the Ministry of Health of Ukraine at the link: https://aisf.dec.gov.ua/
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
From a microbiological point of view, the product should be used immediately after opening the ampoule.
After dilution with 0.9% sodium chloride solution, from a microbiological point of view, the product should be used immediately.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ° C. Do not freeze.
Keep out of reach of children.
Incompatibility
Tyfer should only be mixed with sterile 0.9% sodium chloride solution. No other intravenous solutions or therapeutic agents should be added as there is a risk of precipitation and/or other pharmaceutical interactions. Compatibility with polyethylene and polyvinyl chloride containers has not been studied.
Packaging
5 ml in ampoules. 5 ampoules in a cardboard box.
Vacation category
According to the recipe.
Producer
RAPHARM SA.
Location of the manufacturer and address of its place of business
Zesi Poussi-Xatzi Agiou Louka, Paiania Attiki, TK 19002, P.O. Box 37, Greece.
